{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T05:04:10Z","timestamp":1785301450695,"version":"3.55.0"},"reference-count":74,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>\n                    Recent studies suggest that gasdermin D (GSDMD) pore formation contributes to inflammasome-mediated cytokine release and pyroptosis in podocytes under pathological conditions. However, the molecular mechanisms regulating GSDMD pore formation in these cells remain unclear. Given the established role of the lysosomal acid sphingomyelinase (ASM)\u2013ceramide pathway in obesity-related glomerulopathy (ORG), we investigated whether ASM regulates obesity-induced GSDMD pore formation and pyroptosis in podocytes, thereby influencing the progression of ORG. We found that podocyte-specific Smpd1 (the gene encoding ASM) overexpression markedly enhanced high-fat diet (HFD)-induced NLRP3 inflammasome activation, GSDMD N-terminal fragment (GSDMD-NT) generation, and pyroptosis in glomeruli of Smpd1\n                    <jats:sup>trg<\/jats:sup>\n                    \/Podo\n                    <jats:sup>cre<\/jats:sup>\n                    mice compared to wild-type controls. Pharmacological inhibition of ASM or the NLRP3 inflammasome attenuated these pathological changes in obese mice. In contrast, inhibition of GSDMD pore formation with disulfiram (DIS) prevented HFD-induced pyroptosis without affecting NLRP3 inflammasome activation. Consistently, obesity-induced podocyte injury and glomerulosclerosis were exacerbated by ASM overexpression but alleviated by inhibition of ASM, the NLRP3 inflammasome, or GSDMD pore formation. Using primary podocytes isolated from wild-type, Smpd1 knockout (Smpd1\n                    <jats:sup>-\/-<\/jats:sup>\n                    ), and Smpd1\n                    <jats:sup>trg<\/jats:sup>\n                    \/Podo\n                    <jats:sup>cre<\/jats:sup>\n                    mice, we further demonstrated that palmitic acid (PA), an obesity-associated lipotoxic factor, induced NLRP3 inflammasome activation, GSDMD pore formation, inflammasome product release, and pyroptosis. These responses were suppressed by Smpd1 deletion but enhanced by ASM overexpression. Confocal and super-resolution microscopy revealed that PA increased the accumulation of autophagosomes containing GSDMD-NT while impairing lysosome\u2013autophagosome fusion, effects that were mitigated by Smpd1 deletion and amplified by ASM overexpression. To further elucidate the underlying mechanism, we examined whether ASM regulates lysosomal TRPML1 channel-mediated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release, thereby controlling lysosome\u2013autophagosome interaction and GSDMD-NT degradation. PA inhibited TRPML1 channel activity in podocytes, an effect that was intensified by ASM overexpression. Furthermore, PA-induced impairment of lysosome\u2013autophagosome interaction and increased GSDMD pore formation were attenuated by the TRPML1 agonist ML-SA5 and exacerbated by the TRPML1 inhibitor ML-SI1. Collectively, these findings indicate that ASM regulates lysosomal function and autophagic degradation of GSDMD-NT, thereby controlling GSDMD pore formation and pyroptosis in podocytes during ORG.\n                  <\/jats:p>","DOI":"10.3389\/fphys.2026.1856233","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T04:48:45Z","timestamp":1785300525000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Podocyte-specific acid sphingomyelinase overexpression promotes gasdermin D dependent pyroptosis by impairing autophagic flux during obesity"],"prefix":"10.3389","volume":"17","author":[{"given":"Dandan","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Medicine, Virginia Commonwealth University","place":["Richmond, VA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Zou","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University","place":["Richmond, VA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethan","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University","place":["Richmond, VA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason M.","family":"Kidd","sequence":"additional","affiliation":[{"name":"Division of Nephrology, School of Medicine, Virginia Commonwealth University","place":["Richmond, VA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyuan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University","place":["Richmond, VA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd W.B.","family":"Gehr","sequence":"additional","affiliation":[{"name":"Division of Nephrology, School of Medicine, Virginia Commonwealth University","place":["Richmond, VA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningjun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University","place":["Richmond, VA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pin-Lan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University","place":["Richmond, VA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangbi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University","place":["Richmond, VA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/j.freeradbiomed.2013.10.009","article-title":"Contribution of endogenously produced reactive oxygen species to the activation of podocyte NLRP3 inflammasomes in hyperhomocysteinemia","volume":"67","author":"Abais","year":"2014","journal-title":"Free Radical Biol. 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